Evaluation of the Effects of Tyrosine Kinase Inhibitors on the Metabolism of Human Tumor Cells using an NMR-based Biochemical Profiling Strategy

Imatinib (Gleevec) is one of the first molecularly targeted cancer therapy drugs, successfully approved for the treatment of chronic myelogenous leukemia. The goal of this project was to assess the metabolic profiles and to gain mechanistic insights into the effects of tyrosine kinase inhibitors on cell metabolism. Most studies were based on nuclear magnetic resonance and mass spectrometry metabolic profiling. Treatment with imatinib induced apoptosis in human leukemia cells. Different stages of apoptotic cell death have been distinguished showing specific metabolic patterns. Imatinib resistant cell lines have shown characteristic profiles in regards to their glycolysis and lipid metabolism. After imatinib withdrawal, resistant cells underwent apoptosis and were regaining some of the properties of their parental clones. These findings may be important in the evaluation, identification, prediction of patients developing resistance and treatment of cancer. Based on these results, metabolic profiling of blood from imatinib-treated patients has the potential to be developed into a diagnostic tool to detect the imatinib resistance at an early stage.